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However, robust biomarkers of GABA\n                    <jats:sub>B<\/jats:sub>\n                    Rs target engagement and sensitivity in humans are lacking. We examined transcranial magnetic stimulation (TMS)\u2013derived cortical inhibition and growth hormone (GH) release as measures of GABA\n                    <jats:sub>B<\/jats:sub>\n                    R function, and whether heavy alcohol use is associated with altered responses to pharmacological GABA\n                    <jats:sub>B<\/jats:sub>\n                    R activation. In a randomized, double-blind, placebo-controlled crossover study, 31 healthy volunteers (16 heavy drinkers, 15 light drinkers) received baclofen 30\u2009mg, baclofen 60\u2009mg, or placebo across three sessions. Long-interval intracortical inhibition (LICI), short-interval intracortical inhibition, and intracortical facilitation were assessed with paired-pulse TMS at baseline and ~60\u2009min post-dose. Baclofen blood concentrations and plasma GH levels were measured. Baclofen produced dose-dependent increases in GH release, confirming neuroendocrine GABA\n                    <jats:sub>B<\/jats:sub>\n                    R engagement. The LICI response to baclofen differed between groups: In light drinkers, baclofen at 30\u2009mg potentiated LICI, and a similar potentiation was seen at 60\u2009mg, indicating that a plateau may have been reached. In contrast, in heavy drinkers, a potentiation of LICI similar to that in light drinkers was seen at 30\u2009mg baclofen, but was absent at the 60\u2009mg dose despite comparable pharmacokinetics, suggesting altered GABA\n                    <jats:sub>B<\/jats:sub>\n                    R function. Effects were selective for GABA\n                    <jats:sub>B<\/jats:sub>\n                    R\u2013mediated inhibition, with no consistent modulation of short-interval intracortical inhibition or corticospinal excitability. Acute baclofen administration reveals altered GABA\n                    <jats:sub>B<\/jats:sub>\n                    R sensitivity in heavy drinkers, with preserved responses at lower doses but reduced response under stronger agonist stimulation. LICI and GH release provide complementary biomarkers of central and peripheral GABA\n                    <jats:sub>B<\/jats:sub>\n                    Rs engagement and may support translational development of mechanism-based treatments for AUD.\n                  <\/jats:p>","DOI":"10.1038\/s41398-026-04530-4","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:23:41Z","timestamp":1792715021000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Altered GABAB receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled experimental medicine trial"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3280-1895","authenticated-orcid":false,"given":"Chiara","family":"Montemitro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"Donahue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Costumati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Maruottolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Terezza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Sjoberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5972-0913","authenticated-orcid":false,"given":"Irene","family":"Perini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Roman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7886-631X","authenticated-orcid":false,"given":"Fredrik C.","family":"Kugelberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2706-2482","authenticated-orcid":false,"given":"Markus","family":"Heilig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"key":"4530_CR1","unstructured":"World Health Organization W. 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